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Minority report: the intestinal mycobiota in systemic infections

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Minority report: the intestinal mycobiota in systemic
infections
Thierry Rolling1,2,3, Tobias M Hohl1,2 and Bing Zhai1,2,3
Compared to bacteria, fungi often exhibit a lower abundance
and a higher temporal volatility in the intestinal microbiota.
Analysis of fungi in the microbiota (mycobiota) faces technical
limitations with tools that were originally developed for
analyzing bacteria. Dysbiotic states of the intestinal mycobiota,
often associated with disruption of the healthy bacterial
microbiota, are characterized by overgrowth (domination) of
specific fungal taxa and loss of diversity. Intestinal domination
by Candida species has been shown to be a major source of
Candida bloodstream infections. Fungal dysbiosis is also linked
to the development and treatment response in non-fungal
infections, for example Clostridioides difficile colitis and HIV.
Further research is needed to define the contribution of
intestinal mycobiota to human fungal and non-fungal
infections.
Addresses
1 sent core mycobiota species.
Infectious Disease Service, Department of Medicine, Memorial Hospi-
tal, New York, NY, USA
2
Immunology Program, Sloan Kettering Institute, Memorial Sloan
Kettering Cancer Center, New York, NY, USA
Corresponding authors:
Rolling, Thierry (rollingt@mskcc.org), Zhai, Bing (zhaib@mskcc.org)
3
These authors contributed equally to this manuscript.
Current Opinion in Microbiology 2020, 56:1–6
This review comes from a themed issue on Microbiota
Edited by Iliyan D Iliev
https://doi.org/10.1016/j.mib.2020.05.004
1369-5274/ã 2020 Elsevier Ltd. All rights reserved.
Introduction
The human intestinal microbiota is a complex reservoir of
viruses, bacteria, archaea, fungi, and protozoa. The
impact of the bacterial microbiota on systemic infections,
especially in allogeneic hematopoietic cell transplant
(allo-HCT) patients, has been extensively investigated
[1–5]. In contrast, investigations on the impact of the
fungal compartment of the intestinal microbial flora (i.e.
mycobiota) have only started recently, in part because
fungi generally represent a minor microbial component in
the intestinal niche. In this review, we discuss features of
the human intestinal mycobiota and technical challenges
in its analysis. We focus on summarizing recent research
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developments that link the mycobiota to various human
infectious diseases.
Demographics of the human mycobiota
Current analytical tools for microbiota largely rely on
next-generation sequencing techniques and were initially
developed for analyzing bacteria. These tools have been
adapted to explore the demographics of the mycobiota.
Internal transcribed spacer 1 and 2 (ITS1 and ITS2)
regions of fungal ribosomal DNA are both common
targets in amplicon-based sequencing method and have
provided similar observations [6–8]: In the healthy human
gastrointestinal tract, the most common fungal taxa are
yeasts such as Candida, Saccharomyces, and Malassezia and
filamentous fungi such as Aspergillus, Cladosporium, and
Penicillium. Collectively, these fungal constituents repre-
Shotgun metagenomics sequencing is another commonly
used methodology for microbiota analysis and provides
reads of the total microbiota without a potential bias from
targeted PCR amplification. Shotgun sequencing of
healthy donor samples within the Human Microbiota
Project confirmed the fungal composition obtained by
ITS sequencing [7]. Although the presence of many
species detected in sequencing data can be verified by
cultivation methods [6], a recent study showed that a
considerable portion of recovered fungal DNA from
healthy human fecal samples were in fact derived from
food or other transient contents [9

]. This study corre-
lated a reduction in fecal Candida albicans levels with an
increase in the frequency of oral hygiene. These observa-
tions suggest that core mycobiota species have a higher
volatility than the core bacterial microbiota in the healthy
human gut.
In contrast, in patients with a high risk of fungal infection,
such as allogeneic hematopoietic cell transplant (allo-
HCT) recipients, longitudinal sampling of fecal speci-
mens demonstrated that certain Candida species could
rapidly expand and dominate the intestinal mycobiota,
which precedes systemic fungal infections [10

]. There-
fore, the intestinal mycobiota is characterized by distinct
patterns and constituents under different pathological
conditions.
Current limitations of mycobiota analysis
Metagenomics data in analyzing bacterial microbiota
provide unbiased read numbers of different taxa. They
also allow a functional characterization of the community,
Current Opinion in Microbiology 2020, 56:1–6
2 Microbiota
for example by determining the frequency of drug resis-
tance genes or of genes implicated in metabolic pathways.
However, this method is impractical for detailed charac-
terization of the mycobiota. Multiple studies have shown
that less than 0.1% of shotgun reads from healthy human
fecal samples aligned to fungal genomes [7,11], ranging
from a few hundred to several thousand reads (Figure 1).
Even in a fecal sample with a drastic expansion of Candida
parapsilosis, in which nearly half of the shotgun reads
mapped to one dominant fungal species, the fungal
sequences (8.4  104 reads, 8.4 Mb sequence size) did
not amount to a full coverage of the C. parapsilosis genome
(13 Mb). In general, shotgun sequencing fails to provide
sufficient fungal reads for robust compositional or func-
tional mycobiota analysis. An alternative approach for
functional analysis would be to isolate the fungus from
fecal samples and to perform whole genome sequencing
on the isolates. This approach would bypass the issue of
sequencing depth with fungal genomes but is only appli-
cable to viable fungal cultures from fecal samples.
Given the limitations of shotgun metagenomics, current
characterization of the mycobiota relies on ITS amplicon-
based methods. Although the strategy of fungal ITS
sequencing is analogous to the bacterial 16S sequencing,
fungal sequence analyses encounter technical issues
unprecedented in bacterial sequencing analyses. While
the tandem repeats of rDNA operons vary between 1–15
copies in different bacterial species [12], this variation
ranges between 14–1442 copies in fungal species [13]. An
ideal mycobiota pipeline would normalize the relative
abundance of each species according to the rDNA copy
numbers. However, this normalization is problematic
given the lack of a reference copy number for all fungal
species. Meanwhile, unlike the largely uniform length of
Figure 1
108
non-Fungi
107
Fungi
106
# of Reads
105
104
103
102
101
100
A B
Current Opinion in Microbiology
The fungal reads and non-fungal reads in metagenomic sequencing
data of human fecal samples (A) without Candida domination, and (B)
with Candida domination. Sample B was collected from a patient with
active candidemia. The fungal reads account for <0.01% of total
reads in sample A, and close to 50% of total reads in sample B.
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16S amplicons in bacteria, the ITS1 amplicons from
different fungal species ranges from less than 200 bp to
over 500 bp in length [14]. Since the widely used Illumina
Miseq platform preferentially sequences smaller DNA
fragments [15], fungal species with long ITS regions (e.g.
Saccharomyces cerevisiae [16]) can be underrepresented in
the final data output. The effect of this underrepresenta-
tion will be lower in samples characterized by exponential
overgrowth of specific fungal species than in samples that
contain a diverse mycobiota.
Although new sequencing strategies, for example full-
length rDNA sequencing [17] may bypass the size limita-
tions of the Illumina platform, at the present time ampli-
con-based sequencing is still the best approach to char-
acterize the intestinal mycobiota. Due to the limitations
of the ITS sequencing pipeline and the inherently higher
variability of the intestinal mycobiota, a single sampling
timepoint may not reflect the dynamic nature of intestinal
mycobiota and yield spurious findings in clinical studies.
Instead, researchers should focus on longitudinal collec-
tion of patient samples to provide a dynamic view of
intestinal mycobiota and to reduce sampling noise in the
analysis.
Simultaneous analysis of intestinal fungal and
bacterial flora
As discussed above, the mycobiota represents a minority
of the total intestinal flora. In most instances, bacteria,
especially anaerobes, are the major constituents in the
intestinal niche. Researchers have associated the pres-
ence of anaerobes with intestinal colonization resistance
to fungi, particularly Candida species. Consistent with this
idea, prior exposure to broad-spectrum anti-bacterial anti-
biotics increased the risk of developing candidemia [18].
In a murine model, administration of antibiotics was
required for intestinal C. albicans colonization and dis-
semination [19]. A follow-up study showed that the
anaerobic bacteria, Blautia producta (Family: Lachnospir-
aceae) and Bacteroides thetaiotamicron (Phylum: Bacteroi-
detes), conferred colonization resistance against C. albicans
[20]. Clinical datasets agreed with these laboratory stud-
ies and demonstrated that human intestinal samples with
Candida species expansion exhibited a significant reduc-
tion in these bacterial taxa [10

,21,22]. These findings
point to cross-kingdom interactions between bacteria and
fungi in the intestinal microbiota. Therefore, it is crucial
to analyze fungal and bacterial dynamics in parallel to
assess complementary and antagonistic functions of
members of both kingdoms in the same ecologic niche.
The mycobiota and fungal bloodstream
infections
Candida species cause over 20 000 bloodstream infection
cases per year in the United States alone [23]. Even with
contemporary antifungal drugs, fungus-attributable mor-
tality is higher than 25% [23,24]. Patients in intensive care
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 The intestinal mycobiota and Systemic Infections Rolling, Hohl and Zhai 3
units and immunosuppressed patients, especially those
with prolonged neutropenia, are at an increased risk of
invasive candidiasis [25]. Early identification of high-risk
patients and preemptive treatment may reduce Candida-
related morbidity and mortality [25].
The observation that ingestion of a high dose of live C.
albicans leads to candidemia in a healthy volunteer raised
the hypothesis of an intestinal source for Candida blood-
stream infections [26]. Further studies showed that Can-
dida bloodstream infections are associated with a high
absolute Candida intestinal burden, and that Candida can
be detected in stool samples before the development of a
bloodstream infection in neutropenic patients and in
neonates (systematically reviewed in Ref. [27]).
The intestinal Candida reservoir was confirmed to be an
important source for Candida bloodstream infections by
ITS1 sequencing of longitudinally collected fecal sam-
ples in a case-control studies of allo-HCT patients [10

].
All but one of patient in the Candida bloodstream infec-
tion group experienced a marked intestinal expansion,
both in terms of relative and absolute abundance, of
corresponding Candida species (C. parapsilosis complex
species and C. albicans) before bloodstream infection.
Similar levels of fungal dysbiosis were not observed in
control patients during the study period. Whole genome
sequencing of recovered Candida isolates confirmed the
similarity of strains found in paired stool and blood
samples from individual patients. Therefore, the intesti-
nal Candida expansion could serve as a biomarker to help
identify patients at high risk for systemic candidiasis.
This unusual expansion of specific Candida species dur-
ing allo-HCT was influenced by multiple factors. First,
the expansion of Candida was associated with the loss of
the intestinal bacterial density and diversity, especially of
the anaerobes. The dysbiosis of the anaerobic community
was linked to the prolonged administration of broad-
spectrum antibiotics (Figure 2). Second, C. parapsilosis
complex species were frequently observed as the driver of
intestinal domination and causative agent of bloodstream
infections in this cohort. This predominance may be
associated with the use of antifungal prophylaxis with
micafungin during the first week of allo-HCT, since C.
parapsilosis complex species are more resistant to mica-
fungin than other Candida species [28].
Beyond external factors such as administration of anti-
biotics, a recent study proposed a pathogenic synergy
between bacterial and fungal pathogens at the onset of
systemic candidiasis [29
]. In a murine model, C. albicans
gavage and colonization induced a reduction in oral and
intestinal bacterial diversity, specifically with an over-
growth of Enterococcus spp. in both sites. This observation
suggested that a high burden of Enterococci diminished
oral mucosal integrity and facilitated C. albicans invasion.
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Figure 2
Anti-anaerobic antibiotcs
Fungi
Relative abundance
Fungal BSI
Anaerobes
Time
Current Opinion in Microbiology
The dynamics of intestinal fungal and bacterial flora in the context of
fungal bloodstream infection. This abstractive figure was plotted by re-
analyzing data from a previously published study [10

].
This hypothesis requires further exploration in relevant
clinical studies.
The mycobiota and C. difficile infection
C. difficile is the main cause of nosocomially acquired
diarrhea (C. difficile infection, CDI) [30,31]. Broad-spec-
trum antibiotic use and the ensuing disturbances in the
bacterial microbiota predispose patients to CDI [32,33].
Three studies have shown differential enrichment of
multiple fungal taxa in patients with CDI by association
analyses [34–36]. A limitation of these studies is their low
sample size (10–18 patients with CDI) and the possibility
of an inflated type I error due to multiple testing. Addi-
tionally, the clinical relevance of the reported taxa enrich-
ment (such as Helotiales and Byssochlamys) is unclear, as
they are not generally considered as part of the core
mycobiota [37].
A randomized controlled trial of fecal microbiota transfer
(FMT) for the treatment of CDI showed that CDI
patients had a higher baseline (before FMT) intestinal
fungal load with lower fungal alpha-diversity than healthy
controls, mainly due to an enrichment in C. albicans [38
].
FMT non-responders had a lower fungal diversity with a
higher abundance of C. albicans compared to responders
(post FMT). This finding was possibly linked to a reduc-
tion in bacterial taxa that conferred Candida colonization
resistance (specifically Lachnospiraceae and Bacteroidetes
[20]) in the non-responders. Similarly, in a study compar-
ing fidaxomicin to vancomycin for CDI, Candida intesti-
nal colonization was more frequently observed in the
vancomycin arm [39], since fidaxomicin and not vanco-
mycin was known to spare Bacteroides [40]. Collectively,
these findings were consistent with idea that C. albicans is
not directly associated with CDI but rather represents a
marker for bacterial dysbiosis observed in CDI.
Current Opinion in Microbiology 2020, 56:1–6
4 Microbiota
On the other hand, administration of C. albicans prior or
concomitant with FMT reduced FMT efficacy in a
murine model of CDI [38
]. This result suggests that
intestinal colonized C. albicans may directly influence the
efficacy of FMT. In another study, pre-colonization with
C. albicans prolonged mouse survival after induction of
CDI, without affecting C. difficile growth or toxin titers.
The improved survival was linked to an enhanced pro-
tective IL-17 response in Candida-colonized mice [41].
These mouse data suggest differential effects of C. albi-
cans on CDI outcomes, based on the timing of Candida
administration and study setting and will require valida-
tion in human cohorts.
The mycobiota and HIV infection
Advanced HIV infection with low CD4 T-cell counts is a
known risk factor for opportunistic fungal infections.
Several studies suggest that patients infected with HIV
have increased serum levels of beta-D-glucan (BDG, a
fungal cell wall component) compared to non-infected
controls [42
,43]. Elevated BDG levels are associated
with immune activation and high circulating inflamma-
tory markers in these patients [44,45]. This observation
led to the hypothesis that fungal translocation from the
gut or other mucosal surfaces could lead to immune
activation and disease progression in HIV patients, simi-
larly to what has been postulated for bacteria [46,47]. This
hypothesis will need further validation due to a lack of
data on the intestinal mycobiota in HIV patients [48].
Future outlook
For many gastrointestinal infections, such as spontaneous
peritonitis [49], cholecystitis [50], and superinfected pan-
creatic pseudocysts [51], fungi are well-known causative
pathogens. The gastrointestinal mycobiota appears to be
a likely source for many of these infections. Longitudinal
sampling of intestinal or fecal specimens from these
patients may facilitate monitoring mycobiota dynamics
and may help provide more definitive answers about a
causal link. In the future, it will be imperative to analyze
the intestinal mycobiota in parallel with bacterial flora to
reveal comprehensive cross-kingdom microbial interac-
tions in this complex niche and to define their impact on
human disease development.
Conflict of interest statement
Nothing declared.
Acknowledgements
This work was supported by a Geoffrey Beene Foundation Award (to T.M.
H.), a Burroughs Wellcome Fund Investigator in the Pathogenesis of
Infectious Diseases Award (to T.M.H.), National Institutes of Health grants
(nos. P30 CA008748 to the MSKCC, R01 AI093808 and R01 AI 139632 to
T.M.H.), and a Deutsche Forschungsgemeinschaft (German Research
Foundation) fellowship grant (no. RO5328/2-1 to T.R.).
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